Medicines for injection are not always available from the manufacturer in a ready-to-use form. Therefore, many injections need to be prepared before they can be administered.
The process of preparation may be straightforward, for example a simple dilution, or complicated, for example involving complex calculations, or several manipulations. There are the risks of error in the calculations and during the manipulations involved, and risks of microbial and particulate contamination. The nature of the medicine and the clinical condition of the patient may affect the degree of the overall risk.
The risk of contamination is higher when injections are prepared in environments without suitable controls. Over the past thirty years, surveys on intravenous medicines prepared in near-patient areas have shown a range of contamination rates ranging from 2 to 15% (average 8%). Although most of the contamination does not lead to sepsis, the nature of the contaminating organism cannot be predicted. Therefore the risk of serious sepsis cannot be discounted, particularly if the patient is immunocompromised, or if the injection solution supports bacterial growth.
Therefore there is an increasing need for liquid pharmaceutical compositions in a ready-to-use form, i.e. ready for injection. These kinds of pharmaceutical compositions are normally sold in suitable sterile containers like vials, pre-filled syringes, ampoules, small bottle, tubues or cartridges for autoinjectors.
The preparation of liquid protein formulations for pharmaceutical compositions in a ready-to-use form is generally interfered by the low stability of the protein. In fact, it is known that proteins in the purified form are highly susceptible to degradation, even due to the normal activity of atmospheric agents. This particularity becomes even more evident for proteins produced according to recombinant DNA techniques.
The stability problem is particularly felt for interferon-β formulations, which do not comprise human serum albumin (HSA) as stabilizing agent. Nowadays formulations without HSA are preferred because HSA has two main drawbacks: the first is related to its extraction from human blood and, hence, the possibility of infection transmission, the second refers to its high cost due to its low availability.
Moreover the liquid pharmaceutical compositions may be for single-dose use or for multiple-dose use. In particular, when multi-dose are prepared, it may become necessary to add some additional excipients, which are the preservatives or bacteriotastic agents, to prevent microbial contamination after the container is opened or perforated by a needle due to repeated administrations from the same container.
Although the use of such bacteriostatic agents is necessary for the reason above, it has a negative effect on proteins stability. Because of this, the amount of bacteriostatic agents used in the multidose protein formulation has to be very low. In this case, besides the absence of contamination is not highly guaranteed, the proteins are not stable for the intended use.
To well understand the protein stability problem in the formulations for a multidose product, it has to be underlined the importance that multidose products have in the current pharmaceutical market. In fact, in the most of therapies the liquid pharmaceutical protein formulations have to be injected very often. For instance, liquid interferon-beta formulations for the treatment of multiple sclerosis have to be administered every given day to once a week depending on both the kind of interferon-beta used and if the injection is intramuscular or subcutaneous.
Because of such a frequent use of the formulations, in the last years the liquid pharmaceutical protein formulations are prepared as multidose formulations in containers that the patient can use also by using an injector device. As it is easy to understand, multidose formulations will ease the patient life.
Therefore, the need was felt to find specific conditions for obtaining liquid protein pharmaceutical composition ready for injection, having an improved stability, and being usable for both monodose and multidose use.